A Phase 1/2 Study of SY-12321 in Patients With ALK-positive Advanced Malignancies

Inclusion Criteria:

* Trial participant voluntarily participates in this study and provides signed written informed consent form (ICF).
* Histologically or cytologically confirmed advanced malignancy (locally advanced unresectable or metastatic).
* Trial participant is aged ≥ 18 years at the time of signing the ICF.
* For trial participants previously treated with an ALK-TKI: subjects are eligible for enrollment if they have a report of ALK-positive result from local laboratory testing \[fluorescence in-situ hybridization (FISH), immunohistochemistry (IHC) (Ventana assay), reverse-transcription polymerase chain reaction (RT-PCR), next-generation sequencing (NGS), and other assays\] using tumor tissue or blood sample obtained within 1 year prior to informed-consent signature. In the absence of such positive report, subjects must provide either non-irradiated archival tissue (collected within 1 year) or fresh biopsy tissue, or fresh blood sample (fresh biopsy tissue and fresh blood are preferred). ALK positivity (ALK fusion and/or other meaningful mutations) must be confirmed by NGS testing performed at the central laboratory for eligibility. For trial participants with no prior ALK-TKI treatment: subjects are eligible for enrollment if they have a prior report of ALK-positive result from local laboratory testing of tumor tissue or blood sample. In the absence of such positive report, subjects must provide either non-irradiated archival tissue or fresh biopsy tissue, or fresh blood sample (fresh biopsy tissue and fresh blood are preferred). ALK positivity must be confirmed by NGS testing performed at the central laboratory for eligibility.

Note: Requirements for tumor tissue and blood sample testing are detailed in the \*Central Laboratory Operations Manual.

* Phase Ia will enroll trial participants with ALK-positive advanced malignancies who are pretreated. Pretreated is defined as disease progression or intolerance following standard systemic anti-tumor therapy for advanced disease (recommended by clinical oncology practice standards including Chinese Society of Clinical Oncology (CSCO) guidelines and expert consensus); intolerance is defined as recurrence of Grade ≥3 adverse events despite adequate symptomatic treatment with well-documented evidences (corresponding laboratory findings or original medical records from that episode). Phase Ib will enroll two cohorts: Cohort 1: ALK-positive advanced NSCLC previously treated with any second- and/or third-generation ALK-TKI (including investigational agents not yet marketed); Cohort 2: Other pretreated ALK-positive advanced malignancies. Phase Ⅱ will enroll five cohorts: Cohort 1: ALK-positive advanced NSCLC previously treated with any second-generation ALK-TKI (including investigational agents not yet marketed); Cohort 2: ALK-positive advanced NSCLC previously treated with any third-generation ALK-TKI (including investigational agents not yet marketed); Cohort 3: ALK-positive advanced NSCLC previously treated with both second- and third-generation ALK-TKIs (including investigational agents not yet marketed); Cohort 4: ALK-positive advanced NSCLC without prior exposure to any ALK-TKI (including investigational agents not yet marketed); Cohort 5: Other ALK-positive advanced malignancies.
* At least one measurable extracranial target lesion per RECIST Version 1.1 (for solid tumors) or other standard tumor response assessment criteria (e.g., the Lugano criteria for trial participants with lymphoma). For previously irradiated lesions, such lesions may serve as target lesions only if clear progression has occurred after radiotherapy.
* Expected survival \> 3 months.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate organ function as defined below:

Liver function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3× upper limit of normal (ULN), or ≤ 5× ULN if liver metastasis is present. Total bilirubin (TBIL) ≤ 1.5× ULN, or ≤ 3× ULN if liver metastasis or Gilbert's syndrome is present.

Pancreatic function: serum total amylase ≤ 1.5 × upper limit of normal (ULN); serum lipase ≤ 1.5 × ULN. (If serum total amylase \> 1.5 × ULN: enrollment is permitted provided that the trial participant is willing to undergo additional pancreatic amylase testing and the result is within the ULN; enrollment is not allowed if a pancreatic-amylase result within the ULN cannot be obtained.) Bone marrow function (No blood products, hematopoietic growth factors, or other treatments for hematological abnormalities within 7 days prior to testing): Absolute neutrophil count (ANC) ≥ 1.5×10\^9/L. Platelet count (PLT) ≥ 75×10\^9/L. Hemoglobin (Hb) ≥ 90 g/L.

Renal function: Creatinine level less than 1.5×upper limit of normal (ULN) or Creatinine clearance ≥ 50 mL/min (according to the Cockcroft and Gault formula).

Coagulation function: Prothrombin time (PT) or International Normalized Ratio (INR) ≤ 1.5× ULN (except for subjects on anticoagulation therapy).

10.Female participants of child-bearing potential must have a negative serum pregnancy test result within 7 days prior to the first study drug administration. Male/female participants with reproductive potential and their partners agree to use highly effective contraceptive measures from the time of screening until at least 3 months after the last study drug dose \[1. Abstinence (acceptable only if it is part of the participant's usual lifestyle); 2. Hormonal contraception (oral, patch, ring, injection, implant) combined with male condoms. This contraceptive method must be initiated at least 30 days before the first study drug administration; otherwise, another acceptable contraceptive method shall be adopted; 3. Intrauterine device combined with male condoms\].

Exclusion Criteria:

* Presence of known major driver gene alterations (identified in the participant's current genetic testing report) other than ALK, including but not limited to EGFR, MET (note: including overexpression), ROS1, RET, NTRK, KRAS, etc. For other co-mutation profiles, enrollment eligibility may be discussed with the sponsor.
* Prior treatment with any fourth-generation ALK inhibitors (including investigational agents).
* Known history of allergy to any active ingredient or excipient in SY-12321 capsules.
* Received the following treatments prior to the first dose of SY-12321 capsules:

Nitrosoureas or mitomycin C administered \< 6 weeks before the first dose of study drug; platinum agents, pemetrexed, paclitaxel and other chemotherapeutic agents administered \< 2 weeks (or 5 half-lives, whichever is shorter) before the first dose of study drug; small-molecule targeted agents administered \< 2 weeks (or 5 half-lives, whichever is shorter) before the first dose of study drug; anti-tumor hormonal therapy, traditional Chinese medicines/Chinese patent medicines with anti-tumor indications administered \< 2 weeks before the first dose of study drug; radiotherapy administered \< 4 weeks before the first dose of study drug (or \< 2 weeks for palliative stereotactic radiotherapy not involving the chest, abdomen or pelvis); immunotherapy, biotherapy, and other investigational medicinal products administered \< 4 weeks before the first dose of study drug; radioactive seed implantation, radionuclide therapy, and cell therapy (e.g., CAR-T, stem-cell transplantation, etc.) administered \< 3 months before the first dose of study drug; major surgical procedures (excluding central venous catheter placement, bone-marrow aspiration and biopsy, and gastric tube placement) performed \< 4 weeks before the first dose of study drug.

* Adverse reactions from prior anti-tumor therapy have not recovered to Grade ≤ 1 as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 6.0 (except for toxicities judged by the investigator to pose no safety risk, such as alopecia, Grade 2 peripheral neuropathy, and specific laboratory parameters specified in Inclusion Criterion 9).
* Presence of other malignant neoplasms apart from the tumor under investigation in this study (exceptions: malignancies cured with no recurrence within 2 years prior to study enrollment; completely resected basal-cell and squamous-cell skin carcinoma; completely resected in-situ carcinoma of any type).
* Severe gastrointestinal disorders, including active ulcerative colitis, Crohn's disease, peptic ulcer, gastrointestinal perforation or acute gastrointestinal hemorrhage, or dysphagia, or prior surgical procedures that may substantially impair drug absorption.
* Symptomatic or clinically unstable primary central nervous system (CNS) tumor/metastases, carcinomatous meningitis, leptomeningeal carcinomatosis/metastases, or spinal-cord compression. Note: Stable CNS disease is defined as no radiological evidence of progression (new or enlarging brain metastases) for at least 4 weeks prior to the first study drug dose; no CNS surgery within 4 weeks before first dosing; no whole-brain radiotherapy within 4 weeks before first dosing; no stereotactic radiosurgery (SRS) within 2 weeks before first dosing; and symptomatic treatments such as steroids and mannitol have been discontinued for 2 weeks or maintained at a stable dose before first dosing.
* Presence of Grade ≥ 2 cataract, or Grade ≥ 2 keratitis/corneal ulcer.
* Active infection requiring systemic anti-infective therapy within 2 weeks prior to the first dose of investigational medicinal product.
* Active hepatitis B: positive hepatitis B surface antigen (HBsAg) with HBV-DNA ≥2000 IU/mL; active hepatitis C: positive HCV antibody with HCV-RNA ≥1000 IU/mL); active syphilis (dual-positive for non-treponemal and treponemal syphilis antibodies); positive HIV antibody, or known history of other immunodeficiency disorders; or prior history of organ transplantation, hematopoietic stem-cell transplantation or bone-marrow transplantation (excluding prior hematopoietic stem-cell transplantation in patients with ALCL).
* Within 3 months prior to signing the informed consent form, presence of severe pulmonary diseases (excluding malignancy) requiring systemic therapy, such as active pulmonary tuberculosis, interstitial lung disease, etc.
* Well-documented prior history of neurological or psychiatric disorders, such as dementia.
* History or abnormalities of severe cardiovascular and cerebrovascular diseases, including but not limited to:

Severe cardiac rhythm or conduction abnormalities, e.g., clinically significant ventricular arrhythmias requiring intervention, grade II-III atrioventricular block; Resting Fridericia-corrected QT interval (QTcF) \> 470 msec (female) or \> 450 msec (male). (If QTcF prolongation is suspected to be drug-induced, participants may be enrolled after pharmacological correction if assessed to be safe and manageable by the investigator); \< 6 months since previous coronary angioplasty or stent implantation; Severe aortic valve stenosis; New York Heart Association (NYHA) class ≥ II heart failure or left ventricular ejection fraction (LVEF) \< 50%; Occurrence of acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade ≥ 3 cardiovascular-cerebrovascular events within 6 months prior to the first study drug dose; Radiological evidence of central nervous system hemorrhage (participants with resolved asymptomatic grade 1 post-surgical hemorrhage sustained for \> 3 months may be enrolled).

* Severe thrombosis, coagulopathy or bleeding diathesis, including arterial or venous thromboembolic events within 6 months before the first dose of investigational medicinal product \[including history of myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep-vein thrombosis, or any other severe thromboembolic events (excluding muscular calf vein thrombosis)\]; any life-threatening bleeding events (requiring blood transfusion, surgical or local intervention, or continuous medical therapy); or lesion invasion of large blood vessels judged by the investigator to confer bleeding risk (excluding lesions encircling less than two-thirds of the vessel circumference).
* Uncontrolled hypertension despite optimal antihypertensive therapy, defined as a mean systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 100 mmHg obtained from three repeated measurements separated by at least 10 minutes.
* Poorly controlled diabetes mellitus \[fasting blood glucose ≥10 mmol/L and/or glycated hemoglobin (HbA1c) ≥8%. Glycated hemoglobin testing is mandatory for patients with a history of diabetes mellitus and optional for patients without\].
* Poorly controlled pleural effusion, ascites or pericardial effusion (poorly controlled is defined as obvious increase in effusion within 2 weeks prior to the first dose of investigational medicinal product, presence of prominent symptoms, or requirement for paracentesis or other interventions).
* Symptomatic hyperthyroidism or hypothyroidism that cannot be controlled as assessed by the investigator.
* Electrolyte disturbances (e.g., hypocalcemia, hypomagnesemia, hypokalemia) that cannot be controlled as assessed by the investigator.
* Use of strong CYP3A inhibitors or strong CYP3A inducers within 1 week prior to the first dose of investigational medicinal product or within 5 half-lives (of strong CYP3A inhibitors or inducers), whichever is longer; or anticipated need for such agents during the study period.
* Pregnant or lactating female subjects.
* Presence of other underlying diseases or medical conditions that may increase the risks associated with investigational medicinal product administration, place the participant at undue risk, confound the interpretation of adverse reactions or adverse events (AEs) of the investigational medicinal product; or poor participant compliance; or any other conditions rendering the participant unsuitable for enrollment as judged by the investigator.